Completed Heart, Stroke & Blood Infection & Immunity

The role of the factor H-related proteins in kidney disease

Funder Wellcome Charity-funded
Recipient organisation Imperial College London
Funding £1.9M
Period Nov 2018 — Nov 2023

In plain English

AI plain-English summary

A handful of immune system proteins, called factor H-related (FHR) proteins, are driving damage in two types of kidney disease that currently have no effective treatments. These proteins are cousins of a well-known regulator called factor H, which normally keeps the immune system’s complement cascade—a part of the body’s defence—from attacking healthy tissue. But FHR proteins do the opposite: they seem to amplify complement attack on the kidney’s filtering units. The problem is that nobody knows exactly how they do this. This research aims to find out. The researcher has created new mouse strains that lack FHR proteins, and will test whether removing them protects against kidney injury in models of IgA nephropathy (a common disease) and C3 glomerulopathy (a rare one). They will also study mutant FHR proteins that cause disease, and work out how complement protein C3 accumulation actually damages kidney tissue. If the work succeeds, it could reveal a way to block FHR proteins therapeutically—a strategy that might be safer for long-term use than shutting down the entire complement system. That would matter for thousands of patients with chronic kidney disease who currently have few options.

View original technical description
The complement factor H-related (FHR) proteins influence susceptibility to kidney and eye (age-related macular degeneration) disease, and to meningococcal infection. The FHR proteins are related to complement factor H (FH), the major negative regulator of complement C3 activation. Unlike FH the biological roles of the FHR proteins remain unclear. Understanding how FHR proteins damage the kidney is very important because they are associated with both rare (C3 glomerulopathy) and common (IgA nephropathy) kidney diseases that lack effective treatments. My key goals are to determine how FHR proteins mediate renal injury and if modulating FHR activity can reduce complement-mediated kidney injury. My experimental program will utilise novel mouse strains, developed during my current fellowship, to determine if absence of FHR proteins reduces kidney injury in experimental nephritis, including IgA nephropathy. I will characterise the mechanisms through which mutant FHR proteins cause C3 glomerulopathy by detailed phenotyping of the first model of FHR-associated C3 glomerulopathy. I will elucidate the mechanism through which accumulation of glomerular C3 causes kidney injury. My program will help us to understand how to manipulate these proteins therapeutically which I predict will reveal a means of modulating complement that is safe and amenable to long-term therapy.

View the original record at the funder ↗

Researchers

Matthew Pickering (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

The pathophysiological role of complement regulation in disease.
The role of FHR4 in renal disease associated with complement C3 deposition.
Evaluation of recombinant complement factor H as therapy for orphan renal diseases Dense Deposit Disease & atypical HUS.
The role and diagnosis of complement dysregulation in disease
Complement-mediated endothelial cell injury and cytoprotection: relevance to the pathogenesis and treatment of atypical HUS.

Original classification

Senior Research Fellowship Clinical Renewal

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.